EP2588086B1 - Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactate monohydrate. - Google Patents
Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactate monohydrate. Download PDFInfo
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- EP2588086B1 EP2588086B1 EP11734043.0A EP11734043A EP2588086B1 EP 2588086 B1 EP2588086 B1 EP 2588086B1 EP 11734043 A EP11734043 A EP 11734043A EP 2588086 B1 EP2588086 B1 EP 2588086B1
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- methylpiperazin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- compositions according to the invention are expressed in percentages by weight based on the total weight of the composition.
- Example 12 A similar formulation as in Example 10 and 11 was prepared comprising 11.3 % MCC 105 and pregelatinized starch 15%, for example Starch 1500, instead of MCC 105 and PVPK30. Tablets failed the friability test, and dissolution was slow in both media even though disintegration time was within 10 min, surprisingly showing that pregelatinized starch might not be appropriate in association with the monohydrate form of the active ingredient.
- Example 13 A similar formulation as example 10 with a drug load of 55% fulfilled both the friability and dissolution tests, despite the disintegration time was 15 min.
- Example 14 corresponds to a formulation similar to the one of Example 13 with a drug load of 55 % wherein Povidone K30 is replaced by Copovidone, e.g.
Description
- The present invention relates to pharmaceutical compositions, in particular to compositions for administering 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monohydrate monolactate and to processes for manufacturing such compositions. Published
PCT application WO 2007/064719 describes pharmaceutical compositions of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one or a pharmaceutically acceptable salt or a hydrate or a solvate. In the embodiments ofWO 2007/064719 the lactic acid salt is an anhydrous crystalline form such as form A. The anhydrous form has the disadvantages that it is not thermodynamically stable during the manufacturing process. - There remains a need for an economical and stable composition which overcomes the disadvantages described above. However the inventors have encountered the problem of providing a formulation comprising the active ingredient in a thermodynamically stable form, while keeping the same bioavailability as the formulation comprising the anhydrous form of the same active ingredient. The formulation according to the present invention is providing a pharmaceutical formulation with a higher drug load having a smaller size and is thus more user friendly.
- The amounts of the excipients and active ingredients in the pharmaceutical compositions according to the invention as disclosed below are expressed in percentages by weight based on the total weight of the composition.
- The pharmaceutical composition of the invention is defined in the claims.
- 4-Amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one or a pharmaceutically acceptable salt or a hydrate or a solvate has the structure shown in Formula I:
U.S. Patent Nos. 6,605,617 ,6,774,237 ,7,335,774 , and7,470,709 , and inU.S. Patent Application Serial Nos. 10/982,757 ,10/982,543 10/706,328 PCT applications WO 2006/127926 andWO2009/l15562
The lactate salt of the compound of Formula I exist in a variety of crystalline forms, including, e.g., an anhydrous form such as form A and the monohydrate form such as form HA, also described as form B inWO 2006/127926 .
In some specific embodiments, the lactic acid salt is a monohydrate crystalline form such as e.g., form HA, also described as form B. Crystalline Form B of the lactic acid salt of a compound of Formula I has an X-ray powder diffraction pattern comprising characteristic peaks, in terms of 2θ, at about 17.6°, about 19.3° and about 26.0°. The X-ray powder diffraction pattern of Form B can further comprises characteristic peaks, in terms of 2θ, at about 23.3°, about 23.5° and about 28.2°. The X-ray powder diffraction pattern of Form B can further comprises characteristic peaks, in terms of 2θ, at about 11.9°, about 15.3°, about 16.1° and about 18.5°. The X-ray powder diffraction pattern of Form B can further comprises characteristic peaks, in terms of 2θ, at about 10.2° and about 12.9°. Crystalline Form B has an X-ray powder diffraction pattern comprising at least 3 characteristic peaks, in terms of 2θ, selected from at about 10.2, about 11.3, about 11.6, about 11.9, about 12.9, about 15.3, about 15.6, about 16.1, about 17.6, about 18.5, about 19.3, about 22.3, about 23.3, about 23.5, about 23.9, about 26.0, about 28.2, about 29.3, about 29.8, about 30.7, about 32.2, about 32.6, about 33.1 and about 34.3°. The X-ray diffraction diagram pattern of Form B is substantially as shown on Figure 6 ofWO 2006/127926 .
The term "disintegrant" is understood to mean a substance or mixture of substances which facilitates disintegration of the composition after administration in order that the active ingredient be released from the composition as efficiently as possible to allow for its rapid dissolution (see e.g., "Remington's Pharmaceutical Science" 18th edition (1990), "The Theory and Practice of Industrial Pharmacy" Lachman et al. Lea & Febiger (1970)).
As disintegrant the composition of the present invention may comprise starches, clays, celluloses, alginates, gums, cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., Kollidon from BASF, e.g., Polyplasdone from International Speciality Products (Wayne, NJ), e.g. Crospovidone XL, cross-linked sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC-DI-SOL from FMC, cross-linked calcium carboxymethylcellulose, soy polysaccharides and guar gum. The disintegrant may be present in an amount from about 0.1% to about 10% by weight of the composition. In one embodiment the disintegrant is present in an amount from about 4% to about 8% by weight of the composition or in an amount of more than 4% to 8%, e.g. 5% to 8% by weight of the composition, e.g. 6% to 8%, e.g. 6.5 to 7.5 %. - The disintegrant is crospovidone, for example Crospovidone XL, which is preferably water insoluble. Ideally the disintegrant rapidly exhibits high capillary or pronounced hydration capacity with little tendency to gel formation. The composition of the invention comprises one or more filler selected from microcrystalline cellulose, e.g. MCC102, MCC 105, MCC 200 and mannitol in a total amount of filler of 30 to 50% in weight wherein the amounts by weight are based on the total weight of the composition.
The composition of the invention may further comprise a binder. Examples of pharmaceutically acceptable binders include, but are not limited to, starches, celluloses and derivatives thereof, e.g., microcrystalline cellulose, e.g., hydroxypropyl cellulose, e.g., hydroxyethyl cellulose, e.g., hydroxypropylmethyl cellulose, sucrose, dextrose, corn syrup, polysaccharides, gelatin, polyvinyl pyrrolidone, copovidone, e.g., Kollidon VA64 from BASF. The binder may be present in an amount from about 0% to about 50%, e.g., 10-40% weight by weight of the composition.
The composition of the present invention may further comprise a lubricant or a glidant. Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, e.g., colloidal silicon dioxide, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose. The lubricant, e.g., may be present in an amount from about 0.1% to about 5% by weight of the composition; whereas, the glidant, e.g., may be present in an amount from about 0.1% to about 10% by weight by weight of the composition, e.g. silicon dioxide may be present in an amount of from 0.5 to 2 % ; magnesium stearate may be present in an amount of from 1 to 4% by weight by weight of the composition. - Other excipients disclosed in the literature, as for instance in Fiedler's "Lexicon der Hilfstoffe", 4th Edition, ECV Aulendorf 1996 and "Handbook of Pharmaceutical Excipients" Wade and Weller Ed.(1994), the contents of which are incorporated herein by reference, may be used in the pharmaceutical compositions according to the invention.
- Mannitol may be used as a filler. Mannitol is a hydrophilic component. Therefore if mannitol comes in contact with water, e.g. gastric juice solubilizes it quickly leaving a porous structure which water can penetrate easily. This has the advantage that it increases the dissolution rate which is a key factor for the immediate release pharmaceutical composition of the present invention.
- In a further aspect the present invention provides a process for the production of the compositions of the invention. The compositions of the invention may be prepared by working up active agent with excipients. The processes provided are dry granulation processes. The dry granulation process provides advantages overcoming drug substance properties such as sticking of the drug substance and excipients during the manufacturing process. Generally, the composition of the invention may be obtained by preparing a mixture of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one, with the above mentioned pharmaceutical excipients, such as filler, additional filler, disintegrant, glidant, lubricant etc. by standard methods, processing the mixture by roller compaction to provide yield a milled granulate and processing the milled granulate into capsules or tablets by standard methods.
- The composition of the invention may be obtained by
- (i) Preparing a mixture of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one, one or more filler, e.g. filler, additional filler, disintegrant and glidant
- (ii) Sieving the mixture of step (i)
- (iii) Lubricating the mixture of step (ii) with a lubricant
- (iv) Processing the mixture of step (iii) by roller compaction
- (v) Blending milled granulate of step (iv) with disintegrant and glidant
- (vi) Lubricating with a lubricant
- (vii) Encapsulation of the mixture of step (vi)
- The composition of the invention may be obtained by
- (i) Preparing a mixture of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one or a pharmaceutically acceptable salt or a hydrate or a solvate, filler, disintegrant and lubricant
- (ii) Sieving the mixture
- (iii) Adding lubricant
- (iv) Processing the mixture of step iii) by roller compaction
- (v) Blending milled granulate of step (iv) with glidant, filler and disintegrant and mixing
- (vi) Lubricating with a lubricant
- (vii) Forming tablets by compression
- (viii) Optionally the tablets may be coated
- The resulting powder blends of step vii) are compressed on either a single punch press (Korsh EKO), 6 station-rotary press (Korsh PH106), 17 station-rotary press (Korsh PH 230) or 43 station-rotary press (Fette PT2090).
- The composition of the invention may be formulated as a gelatine capsule such as a hard gelatine capsule. The hard gelatin capsule, also known as a dry-filled capsule, is composed of two sections, one slipping over the other, thus completely surrounding (encapsulating) the drug formulation.
- The composition of the present invention may be formulated as a tablet.
- In one embodiment, the present invention provides tablet compositions with an average hardness of e.g. from 60 to 250 N, preferably from 110 N to 190 N.
- The particles or granules obtained by the manufacturing processes B as described above, or the tablet, may be coated with a non-functional coating as known in the art, for example hydroxypropylmethyl cellulose (HPMC) coating. Suitable coatings may comprise cellulose or derivatives based coatings, e.g., ethylcellulose, e.g. hydroxypropylmethylcellulose, e.g., carboxymethylcellulose, e.g., hydroxyethylcellulose, e.g., cellulose acetate, e.g., cellulose acetate phthalate, e.g., hydroxypropylmethyl cellulose succinate, methylacrylate or polymethylacrylate, a polymethacrylic acid polymer, e.g., Eudragit
- The utility of the pharmaceutical compositions of the present invention may be observed in standard clinical tests, including bioavailability tests, in, for example, known indications of drug dosages giving therapeutically effective blood levels of the therapeutic compound; for example using dosages in the range of 25 - 1000 mg of therapeutic compound per day or alternative dosing regimens for a 75 kg mammal, e.g., adult human and in standard animal models.
Depending on species, age, individual condition, and the clinical picture in question, effective doses for example weekly doses of about 500 to 4000 mg, of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one or a pharmaceutically acceptable salt or a hydrate or a solvate are administered to a human. - The invention pertains to a pharmaceutical composition comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monohydrate monolactate 40 to 65% by weight, e.g. 50%, one or more filler, for example, microcrystalline cellulose 102, 105, and/or 200, for example MCC 102 and MCC200 or MCC105 and MCC200, crospovidone, e.g. crospovidone XL, in an amount of 5 to 7% by weight, silicon dioxide 1 to 1.5% by weight, magnesium stearate in an amount of 2 to 3% by weight by weight of the total weight of the formulation
- A pharmaceutical composition according to the invention comprising in the intragranular phase 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monohydrate monolactate 40 to 65% by weight, e.g. 50%, one or more filler, for example microcrystalline cellulose or microcrystalline cellulose and mannitol, for example microcrystalline cellulose 102, 105 or mixture thereof, e.g. in an amount of 30 to 50% by weight, crospovidone, e.g. crospovidone XL, in an amount of 2 to 7% by weight, silicon dioxide 0.5 to 1% by weight, magnesium stearate in an amount of 0.1 to 1 % by weight, and in the extragranular phase silicon dioxide for example in an amount of 0.2 to 1 % magnesium stearate in an amount of 1 to 3 % by weight, crospovidone, e.g. crospovidone XL, in an amount of 1 to 5 % by weight by weight of the total weight of the formulation.
- When the composition is a tablet the extragranular phase comprises a filler, e.g. microcrystalline cellulose in an amount of 3 to 7% by weight by weight of the total weight of the formulation.
- A tablet composition according to the present invention comprises in the intragranular phase 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monohydrate monolactate 45 to 65%, e.g. 50% by weight, one or more filler, for example microcrystalline cellulose, for example microcrystalline cellulose 102, 105 or mixture thereof, e.g. in an amount of 30 to 50% by weight, crospovidone, e.g. crospovidone XL, in an amount of 2 to 6% by weight, silicon dioxide 0.5 to 1% by weight, magnesium stearate in an amount of 0.1 to 0.5 % by weight, and in the extragranular phase silicon dioxide for example in an amount of 0.2 to 1 % by weight, magnesium stearate in an amount of 1 to 3 % by weight, crospovidone, e.g. crospovidone XL, in an amount of 3 to 5 %, e.g. 4 to 5% by weight, a filler, for example microcrystalline cellulose, for example MCC 200, for example in an amount of 3% to 5% by weight by weight by weight of the total weight of the formulation. The tablets according to the present invention are film-coated tablets.
- A capsule composition according to the present invention comprises in the intragranular phase 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monohydrate monolactate 30 to 50% by weight, e.g. 40 to 42% by weight, one or more filler, for example microcrystalline cellulose, for example microcrystalline cellulose 102, 105, 200, mannitol or mixture thereof, e.g. in an amount of 30 to 50% by weight, crospovidone, e.g. crospovidone XL, in an amount of 4 to 6 % by weight, silicon dioxide 0.5 to 1% by weight, magnesium stearate in an amount of 0.1 to 0.5 % by weight, and in the extragranular phase silicon dioxide for example in an amount of 0.2 to 1 % magnesium stearate by weight in an amount of 1 to 3 % by weight, crospovidone, e.g. crospovidone XL, in an amount of 3 to 5 %, by weight e.g. 4 to 5% by weight, a filler, for example microcrystalline cellulose, for example MCC 200, for example in an amount of 3% to 5% by weight wherein the amounts by weight are based on the total weight of the composition. The tablet is or can be coated, e.g. film-coated.
- Following is a non-limiting description by way of examples.
According to the below examples and to the specification above, the capsule or tablet dose would refer to the weight of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid present in the formulation, for example a 100 mg tablet comprises 100 mg of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid so 128 mg of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid monolactate monohydrate. The percentages in the composition as detailed below are expressed in weight by weight based on the total weight of the tablet and in case of the active ingredient the percentage corresponds to the percentage of the monohydrate monolactate salt thereof present in the composition. -
Component % w/w Compound X 41.29 Microcrystalline cellulose 45.32 Mannitol 3.23 Crospovidone 7.42 Silicon dioxide, e.g Aerosil 0.97 Magnesium stearate 1.78 - A mixture of compound X, microcrystalline cellulose, crospovidone, mannitol and Aerosil is formed. This mixture is sieved and lubricated with magnesium stearate. The mixture is processed by roller compaction. The resulting milled granulate is blended with crospovidone and Aerosil. The mixture is lubricated with magnesium stearate and the mixture is encapsulated.
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Component % w/w Compound X 41.29 41.13 Microcrystalline cellulose 45.32 45.5 Mannitol 3.23 3.22 Crospovidone 7.42 7.49 Silicon dioxide, e.g Aerosil 0.97 0.96 Magnesium stearate 1.78 1.77 - A mixture of compound X, microcrystalline cellulose, crospovidone, mannitol and Aerosil is formed. This mixture is sieved and lubricated with magnesium stearate. The mixture is processed by roller compaction. The resulting milled granulate is blended with crospovidone and Aerosil. The mixture is lubricated with magnesium stearate and the mixture is encapsulated.
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Component % w/w Compound X 49.80 Microcrystalline cellulose 41.50 Crospovidone 5.0 Silicon dioxide, e.g Aerosil 1.2 Magnesium stearate 2.5 - A mixture of compound X, microcrystalline cellulose, crospovidone and Aerosil is formed. This mixture is sieved and lubricated with magnesium stearate. The mixture is processed by roller compaction. The resulting milled granulate is blended with Aerosil and crospovidone. This mixture is lubricated with magnesium stearate. The tablets are formed by compression.
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Component % w/w Compound X 49.80 Microcrystalline cellulose 41.50 Crospovidone 5.0 Silicon dioxide, e.g Aerosil 1.2 Magnesium stearate 2.5 - A mixture of compound X, microcrystalline cellulose, crospovidone and Aerosil is formed. This mixture is sieved and lubricated with magnesium stearate. The mixture is processed by roller compaction. The resulting milled granulate is blended with Aerosil and crospovidone. This mixture is lubricated with magnesium stearate. The tablets are formed by compression.
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Component % w/w Compound X 50.0 Microcrystalline cellulose 30.7 Copovidone, e.g. Kollidon VA64 8.0 Crospovidone 7.0 Silicon dioxide, e.g Aerosil 1.0 Magnesium stearate 2.4 - A mixture of compound X, microcrystalline cellulose, crospovidone, Kollidon VA64 and Aerosil is formed. This mixture is sieved and lubricated with magnesium stearate. The mixture is processed by roller compaction. The resulting milled granulate is blended with Aerosil and crospovidone. This mixture is lubricated with magnesium stearate. The tablets are formed by compression.
- Example 6: Capsules and tablets provide a fast release of the active substance. Dissolution rates are measured in standard dissolution tests, e.g. effected by use of the apparatus 2 (Rotary Paddle) of the USP at 37 degree Celsius in dissolution rate medium A (pH approximately 1.5; 0.04 Molar HCl + 2g/lit NaCl) and in dissolution rate medium B (pH 4.5 acetate buffer) at a stirring rate of 50 rpm and based on the mean of 6 or more e.g., 12 dosage forms.
100 mg capsule dissolution rates for n=6:Time (min) Medium A % released Medium B % released 10 82 65 20 89 76 30 92 77 45 94 86 60 97 88 Time (min) Medium A % released Medium B % released 10 84 59 20 94 72 30 99 76 45 100 81 60 100 84 Time (min) Medium A % released Medium B % released 10 90 80 15 99 88 20 100 89 30 101 92 45 102 94 60 102 96 Time (min) Medium A % released Medium B % released 10 91 87 15 96 91 20 97 94 30 98 95 45 99 97 60 100 97 Time (min) Medium A % released Medium B % released 10 99 90 20 99 94 30 99 95 45 99 93 60 99 94 75 99 94 - The compositions of the invention (the tablet and the capsule) comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid monohydrate have been tested and compared with the formulation described in
WO 2007/064719 using an anhydrous form of the drug substance (formulation Y) in a dog study. The pharmacokinetic parameters Cmax and AUC have been measured. The study has been done with 6 dogs for each formulation using 25 mg formulations. The parameters Cmax and AUC have been found to be comparable.
Cmax (ng/ml)Formulation Y Capsule Tablet Lower 95% CI 7.6 6.2 5.2 Mean 11 10.4 9.4 Upper 95% CI 14.4 14.6 13.5 Formulation Y Capsule Tablet Lower 95% CI 48.3 39.7 32 Mean 67.7 67.5 62.4 Upper 95% CI 87 95.3 92.8 - A total of 21 subjects were randomized to the 2 treatment sequences Day 1 : 500 mg as tablet or 500 mg as capsule, then rest Day 2 until day 8 and Day 9 like Day 1. Out of the total randomized subjects, a total of 17 (81%) received both of the planned doses at 500 mg during cycle 1, and provided evaluable pharmacokinetic data, and included in this analysis.
A formal statistical analysis was performed to estimate the relative bioavailability of the capsule formulation of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one according to the invention as compared to the capsule formulation according toUS2008/0293738 A1 , capsule composition 13. A linear mixed effects model was fitted to the log-transformed PK parameters (AUC0-tlast, AUC0-∞, and Cmax). Included in the model were treatment, period, and sequence as fixed factors and subjects nested within sequences as a random factor.
For the bioavailability analysis, the capsule formulation according to the present invention was the test and the intact capsule formulation was the reference toUS2008/0293738 A1 . The two-sided 90% CI for the least square means of the difference (test - reference) on the log-scale was calculated. This was anti-logged to obtain the point estimates and the 90% confidence interval for the ratio of the geometric means on the untransformed scale.
The summary of the statistical analysis (adjusted geo-means, the geo-mean ratio and the 90% confidence interval) for the PK parameters (Cmax, AUC0-tlast, AUC0-∞), and the median along with the minimum and the maximum range for Tmax is presented in the below table, by treatment group.
The geometric mean ratio for the primary PK parameters and 90% CI comparing (500 mg) tablet versus (500 mg) capsule are listed as follows:AUCinf (hr xng/mL) : 0.88 (0.72 to 1.07) AUC0-tlast (hr xng/mL): 0.96 (0.89 to 1.04) Cmax (ng/mL) : 0.99 (0.91 to 1.08) Ratio of geometric means with (90% CI) of Compound X primary PK parameters (Arm 1) PK set Treatment Comparison 90% CI PK Parameter (unit) Treatment n * Adjusted Geo-mean Comparison Geo-mean Ratio Lower Upper AUC(0-inf) (ng*hr/mL) CSF 6 6402.35 FMI 8 5604.93 FMI:CSF 0.88 0.72 1.07 AUC(0-tlast) (ng*hr/mL) CSF 17 4738.24 FMI 17 4568.27 FMI:CSF 0.96 0.89 1.04 Cmax (ng/mL) CSF 17 192.33 FMI 17 190.47 FMI:CSF 0.99 0.91 1.08 Tmax (hr) CSF 17 7.00 Treatment Comparison 90% CI PK Parameter (unit) Treatment n * Adjusted Geo-mean Comparison Geo-mean Ratio Lower Upper FMI 17 7.00 FMI-CSF 0.00 -4.00 1.95 CSF corresponds to capsules, FMI corresponds to tablets. - The conclusion of this study is that the tablet according to the present invention provides the active ingredient with a bioavailability equivalent to the one of the capsule according to
US2008/0293738 A1 , capsule composition 13, this result was not foreseeable.
8.2 Assessment of bioavailability of the capsule comprising anhydrous monolactate of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one versus capsules comprising monohydrous monolactate of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one (Compound X in the below examples). - A total of 20 eligible patients have been enrolled and randomly assigned into 1 of 2 treatment sequences as presented in the below table.
Cycle 1 Period 1 Period 2 Day 1 Days 2 - 8 Day 9 Sequence 1 500 mg (anhydrous caps) Rest 500 mg (monohydrous caps) Sequence 2 500 mg (monohydrous caps) Rest 500 mg (anhydrous caps)) Treatment Comparison 90% CI PK Parameter (unit) Treatment n* Adjusted Geo-mean Comparison(s) Geo-mean ratio Lower Upper AUC(0-inf) (h.ng/mL) SSF 16 7127.47 FMI 16 6286.50 FMI/CSF 0.88 0.79 0.98 AUC(0-tlast) (h.ng/mL) CSF 16 5577.41 FMI 16 4886.40 FMI/CSF 0.88 0.80 0.95 Cmax (ng/mL) CSF 16 226.29 FMI 16 213.44 FMI/CSF 0.94 0.85 1.04 Tmax (h) CSF 16 6.00 FMI 16 5.04 FMI / CSF 0.00 2.00 CSF corresponds to capsules comprising anhydrous monolactate of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one , FMI corresponds to tablets monohydrate monolactate of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one. AUCinf (hr x xng/mL) : 0.88 (0.79 to 0.98) AUC0-tlast (hr x ng/mL) : 0.88 (0.80 to 0.95) Cmax (ng/mL) : 0.94 (0.85 to 1.04) US2008/0293738 A1 , capsule composition 13 and the capsule according to the present invention. The PK results demonstrate that the two capsules have comparable bioavailability. - Example 9: The following blend made of Compound X active ingredient 36.6 %, MCC 200 40%, mannitol 10%, hydroxypropylcellulose 4%, croscarmellose sodium 6%, silicon dioxide 0.86%, magnesium stearate 2.57 % was compressed into tablets. Besides the slow release profile, the tablet parameters mainly friability were unsatisfactory.
- Example 9bis: The following blend was prepared active ingredient 36.6%, MCC 112 42.6 %, MCC 200 4.8%, PVPK30 4.9%, Crospovidone XL 8%, Silicon dioxide 1.14%, Magnesium stearate 2% and compressed into tablets. The dissolution release profile was faster than for example 8 however the tablets failed the friability test, despite in presence of a binder.
- Example 10: Tablets according have the following composition
The corresponding tablet comprising MCC 101 or MCC 112 instead of MCC 105 and less crospovidone showed sticking to the roller and a lower mean dissolution release in acetate buffer pH4.5 and in SGF at 10 minutes. Therefore, surprisingly in view of the test results, MCC 101 seems to lead to variations with respect to the compaction process in the manufacture of the tablet according to the present invention. - Example 11: A formulation similar to the one of Example 10 was prepared comprising 63% of active ingredient and a corresponding decrease in MCC 105 and increase in the other excipients. The formulation gave satisfactory results from the friability and DT tests, while the dissolution in pH4.5 was low.
- Example 12: A similar formulation as in Example 10 and 11 was prepared comprising 11.3 % MCC 105 and pregelatinized starch 15%, for example Starch 1500, instead of MCC 105 and PVPK30. Tablets failed the friability test, and dissolution was slow in both media even though disintegration time was within 10 min, surprisingly showing that pregelatinized starch might not be appropriate in association with the monohydrate form of the active ingredient. Example 13: A similar formulation as example 10 with a drug load of 55% fulfilled both the friability and dissolution tests, despite the disintegration time was 15 min.
Example 14 corresponds to a formulation similar to the one of Example 13 with a drug load of 55 % wherein Povidone K30 is replaced by Copovidone, e.g. Kollidon VA64 Fine, 8% and the amount of MCC 105 reduced accordingly. The friability was increased as compared to Example 13 and the dissolution rate dropped by 10%, especially at 10 min time point. Surprisingly the dissolution rate was fast despite the disintegration time between 16 to 18 min. Example 15: The formulation has a drug load of 50%, Kollidon VA64 Fine 8 % and the amount of the other excipients. Sticking was observed on the die rollers during roller compaction.
In summary of Examples 14 and 15, Copovidone as excipient did not improve the properties of the formulation contrary to expectations, in terms of friability. -
- This formulation exhibited good processability with no sticking however picking was observed that could be avoided by adding 0.5% of magnesium stearate in the intragranular phase or increasing the compression force.
- In an alternative, the amount of magnesium stearate in the extra granular phase is increased by 0.5% when magnesium stearate is present in the intragranular phase and process was discontinued due to sticking issues.
- Example 17: This formulation corresponds to the formulation of Example 16 where Crospovidone is present in a total of 4%, MCC200 is absent from the extragranular phase and Copovidone is present in an amount of 4 %. Sticking on the roller was observed as well as poor dissolution release and too slow disintegration time.
- This data confirms that Copovidone might not be used in the formulation and could prevent good release profile.
-
- These formulations successfully complied with all tests performed and no issue occurred during the manufacturing process.
- Example 20: Capsules comprising the monolactate monohydrate form of Compound X should have a release profile as close as possible to the one of the capsules comprising Compound X in the anhydrous form. The composition of the formulation also needs to allow running a robust process. Finally the formulation shall meet the standard of stability.
- Surprisingly it was found that the use of Croscarmellose sodium was not suitable as there was an interaction between Compound X monohydrate form and this excipient at pH4.5 which prevents to achieve a satisfactory release profile, i.e. a release profile of about 75 to 80% in a pH4.5 media for 60 min. This was not expected.
- Sticking on the rollers during the process was to be solved. Defective capsules were obtained because of the overfilling of Size 1 capsules during the encapsulation process so this problem was addressed by reducing the full weight.
- Hydroxypropyl cellulose was tested as a filler and the dissolution release was slower. Mannitol up to 10% was included and this had no negative impact on the dissolution release. Surprisingly MCC 101 was found to lead to a poorer release profile of the capsule formulation and this was unexpected for the same reasons as mentioned above, namely that MCC 101 was mentioned in the preparation of the formulation according to
WO2007/064719 .
Claims (12)
- A pharmaceutical composition for oral administration comprisinga) an intragranular phase comprising:4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monohydrate monolactate in an amount of 40 to 65 % by weight,one or more filler selected from microcrystalline cellulose or microcrystalline cellulose and mannitol in an amount of 30 to 50% by weight,crospovidone in an amount of 2 to 7% by weight,silicon dioxide in an amount of 0.5 to 1% by weight,magnesium stearate in an amount of 0.1 to 1% by weight;b) an extragranular phase comprising:wherein the amounts by weight are based on the total weight of the composition.silicon dioxide in an amount of 0.2 to 1% by weight,magnesium stearate in an amount of 1 to 3% by weight,crospovidone in an amount of 1 to 5% by weight;
- The pharmaceutical composition according to claim 1, wherein the composition is formulated as a capsule or a tablet.
- The pharmaceutical composition according to claim 1, wherein the composition is formulated as a tablet, and wherein the extragranular phase comprises a filler which is microcrystalline cellulose in an amount of 3 to 7% by weight of the total weight of the formulation.
- The pharmaceutical composition according to claim 1 or 2, wherein the filler of the intragranular phase is microcrystalline cellulose and mannitol.
- The pharmaceutical composition according to claim 1 wherein the composition is formulated as a tablet and wherein the composition comprisesa) an intragranular phase comprising:4-amino-5-fluoro-3-[6-(4-methylpiperazin-l-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monohydrate monolactate in an amount of 45 to 65 % by weight,microcrystalline cellulose in an amount of 30 to 50% by weight,crospovidone in an amount of 2 to 6% by weight,silicon dioxide in an amount of 0.5 to 1% by weight,magnesium stearate in an amount of 0.1 to 0.5% by weight;b) an extragranular phase comprising:silicon dioxide in an amount of 0.2 to 1% by weight,magnesium stearate in an amount of 1 to 3% by weight,crospovidone in an amount of 3 to 5%,microcrystalline cellulose in an amount of 3 to 5%.
- The pharmaceutical composition according to claim 1 wherein the composition is formulated as a capsule and wherein the composition comprisesa) an intragranular phase
comprising:4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monolactate monohydrate in an amount of 30 to 50 % by weight,one or more filler selected from microcrystalline cellulose, mannitol or a mixture thereof in an amount of 30 to 50% by weight,crospovidone in an amount of 4 to 6% by weight,silicon dioxide in an amount of 0.5 to 1% by weight,magnesium stearate in an amount of 0.1 to 0.5% by weight,b) an extragranular phase comprising:silicon dioxide in an amount of 0.2 to 1% by weight,magnesium stearate in an amount of 1 to 3% by weight,crospovidone 3 to 5%,microcrystalline cellulose in an amount of 3 to 5%. - The pharmaceutical composition according to any one of claims 1 to 6, wherein the microcrystalline cellulose is MCC102, MCC 105 and/or MCC 200.
- The pharmaceutical composition according to any one of claims 1 to 7 wherein the 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one is present in the form of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one monohydrate monolactate is in the form of Form HA.
- A process for the production of a pharmaceutical composition as defined in any one of the preceding claims, wherein the process is a dry granulation process.
- The process according to claim 9, wherein the dry granulation is obtained by roller compaction.
- The process according to claim 9 or 10, wherein the process comprises:i) Preparing a mixture of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one, one or more filler, e.g. a filler, and an additional filler, disintegrant and glidantii) Sieving the mixture of step (i)iii) Lubricating the mixture of step (ii) with a lubricantiv) Processing the mixture of step (iii) by roller compactionv) Blending milled granulate of step (iv) disintegrant and glidantvi) Lubricating with a lubricant.vii) Encapsulation of the mixture of step (vi).
- The process according to claim 9 or 10, wherein the process comprises:i) Preparing a mixture of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one, filler, disintegrant and lubricantii) Sieving the mixtureiii) Adding lubricantiv) Processing the mixture of step iii) by roller compactionv) Blending milled granulate from step (iv) with glidant, filler and disintegrant and mixingvi) Lubricating with a lubricantvii) Forming tablets by compression.
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EP11734043.0A EP2588086B1 (en) | 2010-06-30 | 2011-06-29 | Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactate monohydrate. |
EP18193864.8A EP3446686A1 (en) | 2010-06-30 | 2011-06-29 | Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactate monohydrate |
PL11734043T PL2588086T3 (en) | 2010-06-30 | 2011-06-29 | Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactate monohydrate. |
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EP11734043.0A EP2588086B1 (en) | 2010-06-30 | 2011-06-29 | Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactate monohydrate. |
PCT/EP2011/060949 WO2012001074A2 (en) | 2010-06-30 | 2011-06-29 | Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactate monohydrate. |
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EP18193864.8A Pending EP3446686A1 (en) | 2010-06-30 | 2011-06-29 | Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactate monohydrate |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2013063003A1 (en) | 2011-10-28 | 2013-05-02 | Novartis Ag | Method of treating gastrointestinal stromal tumors |
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US20150202203A1 (en) | 2012-07-11 | 2015-07-23 | Novartis Ag | Method of Treating Gastrointestinal Stromal Tumors |
US9395468B2 (en) | 2012-08-27 | 2016-07-19 | Ocular Dynamics, Llc | Contact lens with a hydrophilic layer |
WO2014058785A1 (en) | 2012-10-10 | 2014-04-17 | Novartis Ag | Combination therapy |
DK3482771T3 (en) | 2013-03-14 | 2023-03-20 | Nestle Sa | PREPARATION OF PEANUT FORMULATIONS FOR ORAL DESENSITIZATION |
US9492535B2 (en) | 2013-03-14 | 2016-11-15 | Aimmune Therapeutics, Inc. | Peanut formulations and uses thereof |
TWI654440B (en) | 2013-11-15 | 2019-03-21 | 美商實體科學公司 | Contact lens with hydrophilic layer |
US20150343075A1 (en) * | 2014-06-02 | 2015-12-03 | Aimmune Therapeutics | Placebo formulations and uses thereof |
AU2015360637B2 (en) | 2014-12-09 | 2019-08-22 | Tangible Science, Inc. | Medical device coating with a biocompatible layer |
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JP2021501763A (en) | 2017-11-02 | 2021-01-21 | アイミューン セラピューティクス,インコーポレイテッド | Oral immunotherapy method |
JP2022532547A (en) | 2019-05-10 | 2022-07-15 | アイミューン セラピューティクス,インコーポレイテッド | Ways to improve the quality of life of patients with peanut allergies |
US10835531B1 (en) | 2019-06-18 | 2020-11-17 | Oncology Venture ApS | Methods for predicting drug responsiveness in cancer patients |
US20230302139A1 (en) * | 2020-07-31 | 2023-09-28 | University Of Florida Research Foundation, Incorporated | Targeted rna degradation allows precision repurposing of protein-targeted small molecule medicines to rna |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5009897A (en) * | 1988-06-24 | 1991-04-23 | Abbott Laboratories | Pharmaceutical granules and tablets made therefrom |
ATE386736T1 (en) | 2000-09-11 | 2008-03-15 | Novartis Vaccines & Diagnostic | METHOD FOR PRODUCING BENZIMIDAZOLE-2-YL - QUINOLINONE DERIVATIVES |
BR0313743A (en) | 2002-08-23 | 2005-07-05 | Chiron Corp | Benzimidazole quinolinones and uses of these |
US20060172006A1 (en) * | 2003-10-10 | 2006-08-03 | Vincent Lenaerts | Sustained-release tramadol formulations with 24-hour clinical efficacy |
GB0504203D0 (en) * | 2005-03-01 | 2005-04-06 | Novartis Ag | Organic compounds |
KR101368519B1 (en) * | 2005-05-23 | 2014-02-27 | 노파르티스 아게 | Crystalline and other forms of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one lactic acid salts |
KR20080039876A (en) * | 2005-07-22 | 2008-05-07 | 미리어드 제네틱스, 인크. | High drug load formulations and dosage forms |
RU2433826C2 (en) * | 2005-11-29 | 2011-11-20 | Новартис Аг | Compositions of quinolinones |
CN101316593B (en) * | 2005-11-29 | 2012-05-02 | 诺瓦提斯公司 | Formulations of quinolinones |
JP2010520881A (en) | 2007-03-09 | 2010-06-17 | ノバルティス アーゲー | Melanoma treatment |
DK2205244T3 (en) | 2007-11-08 | 2013-11-25 | Ambit Biosciences Corp | METHODS FOR ADMINISTRATING N- (5-TERT-BUTYL-ISOXAZOL-3-YL) -N '- {4- [7- (2-MORPHOLIN-4-YL-ETHOXY-) IMIDAZO- [2,1-B] - [1,3] -BENZOTHIAZOL-2-YL] -PHENYL} URINE FOR TREATMENT OF PROLIFERATIVE DISEASE |
AR070924A1 (en) * | 2008-03-19 | 2010-05-12 | Novartis Ag | CRYSTAL FORMS AND TWO SOLVATED FORMS OF LACTIC ACID SALTS OF 4- AMINO -5- FLUORO-3- (5- (4-METHYLIPIPERAZIN-1-IL) -1H- BENCIMIDAZOL-2-IL) QUINOLIN -2- (1H) - ONA |
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EP2558082A1 (en) | 2010-04-16 | 2013-02-20 | Novartis AG | Combination of organic compounds |
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